U.S. provisional application No. 60/513,618, discloses a controlled release sterile injectable aripiprazole formulation in the form of a sterile suspension, and a method for preparing a sterile freeze-dried aripiprazole formulation (employed in forming the injectable formulation) which includes the steps of:
(a) preparing sterile bulk aripiprazole preferably having a desired particle size distribution and mean particle size within the range from about 5 to about 100 microns, more preferably from about 10 to about 90 microns,
(b) preparing a sterile vehicle for the sterile bulk aripiprazole,
(c) combining the sterile bulk aripiprazole and the sterile vehicle to form a sterile primary suspension,
(d) reducing the mean particle size of aripiprazole in the sterile primary suspension to within the range from about 0.05 to about 30 microns, to form a final sterile suspension, and
(e) freeze drying the final sterile suspension to form a sterile freeze-dried suspension of the aripiprazole of desired polymorphic form (anhydrous, monohydrate, or a mixture of both).
In carrying out the above method for preparing the freeze-dried aripiprazole formulation, it is required that everything be sterile so that sterile aripiprazole and sterile vehicle are combined aseptically to form a sterile suspension and that the sterile suspension be freeze-dried in a manner to form sterile freeze-dried powder or cake. Thus, an aseptic procedure is employed to produce sterile bulk aripiprazole of desired mean particle size, and particle size distribution, by crystallization methods as opposed to ball milling. The sterile bulk aripiprazole preferably prepared in step (a) by means of the impinging jet crystallization method, has a desired small particle size and narrow particle size distribution, high surface area, high chemical purity, and high stability due to improved crystal structure.
The impinging jet crystallization utilizes two jet streams that strike each other head-on. One of the streams carries a solution rich in the aripiprazole and the other carries an anti-solvent, such as water. The two streams strike each other which allows for rapid homogeneous mixing and supersaturation due to high turbulence and high intensity of micromixing upon impact. This immediate achievement of supersaturation initiates rapid nucleation. In general, the average crystal size of the aripiprazole decreases with increasing supersaturation and decreasing temperature of the anti-solvent. Therefore, in order to obtain the smallest particle size, it is advantageous to have the highest possible concentration of the aripiprazole rich solution and the lowest temperature of the anti-solvent.
The technique employed for forming sterile bulk aripiprazole is important since particle size of the aripiprazole formulation controls its release profile in the blood system over a period of one month.
It has been found that batch crystallization of aripiprazole produces particles 100 microns. However, in formulating the controlled release sterile aripiprazole injectable formulation discussed above, the particle size of the aripiprazole needs to be 95%≦100 microns. In addition, a narrow particle size distribution is needed to maintain control of the release profile. Milling of batch aripiprazole is undesirable, as a broad particle size distribution will be obtained. Thus, it would be advantageous to employ a technique for preparing sterile bulk aripiprazole which can reduce particle size of aripiprazole to 95%≦100 microns with a narrower particle size distribution than attainable employing batch crystallization.
U.S. Pat. No. 5,006,528 to Oshiro et al. discloses 7-[(4-phenylpiperazino)-butoxy]carbostyrils, which include aripiprazole, as dopaminergic neurotransmitter antagonists.
Aripiprazole which has the structure
is an atypical antipsychotic agent useful in treating schizophrenia. It has poor aqueous solubility (<1 μg/mL at room temperature).
U.S. Pat. No. 6,267,989 to Liversidge, et al. discloses a method for preventing crystal growth and particle aggregation in nanoparticulate compositions wherein a nanoparticulate composition is reduced to an optimal effective average particle size employing aqueous milling techniques including ball milling.
U.S. Pat. No. 5,314,506 to Midler, et al. discloses a process for the direct crystallization of a pharmaceutical having high surface area particles of high purity and stability wherein impinging jet streams are employed to achieve high intensity micromixing of particles of the pharmaceutical followed by nucleation and direct production of small crystals.
U.S. Pat. No. 6,302,958 to Lindrud et al. discloses a method and apparatus for crystallizing submicron-sized crystals of a pharmaceutical composition employing sonication to provide ultrasonic energy in the immediate vicinity of impinging fluid drug and solvent streams so as to effect nucleation and the direct production of small crystals.
U.S. application Ser. No. 10/419,418, filed Apr. 21, 2003 by Chenkou Wei which is based on U.S. Provisional Applications Nos. 60/376,414, filed Apr. 29, 2002 and 60/439,066, filed Jan. 9, 2003 entitled “Crystallization System Using Atomization” discloses a method for crystallizing a pharmaceutical by atomizing one solution and introducing the atomized solution into a vessel containing a second solution where the solutions are mixed to form a product, which does not require post-crystallization milling. This application is incorporated herein by reference.
U.S. application Ser. No. 10/419,647, filed Apr. 21, 2003 by Chenkou Wei which is based on U.S. Provisional Applications Nos. 60/379,351, filed May 10, 2002 and 60/439,057, filed Jan. 9, 2003 entitled “Crystallization System Using Homogenization” discloses a process for crystallizing a chemical material from a first solution and a second solution wherein the first solution is atomized and introduced into a second solution, and the atomized solution and second solution are mixed to form the product. This application is incorporated herein by reference.